Intrinsic Host Defenses Against HIV and Other Retroviruses

Intrinsic host defense: Primates have evolved a number of gene families that limit or restrict retroviral infections. In collaboration with Harmit Malik's lab. We are studying the evolution of function of these intrinsic anti-viral genes. We have found that some of these genes have been rapidly evolving throughout the history of primates and some have been under selective pressure in recent human history.

Apobec3 — The human Apobec3 locus encodes at least 7 proteins that have cytidine deaminase activity that act against retroviruses, endogenous retro-elements in our genome, and some other viruses. However, this locus has been very dynamic over primate evolution and shows genetic evidence of having been repeatedly selected for change over time.  We hypothesize that endogenous or exogenous infections have provided the selective pressure for Apobec3 evolution.   One of these genes, Apobec3H, has undergone a dramatic shift in function in the human/chimp lineage.  In more recent human evolution, however, this gene has been independently lost twice due to destablizing mutations.  We would like to understand the consequences of these changes and the pathogens that drove the selections.

Trim5α — We have found regions of accelerated evolution in the Trim5α protein and have shown that these are the regions that confer specificity for which viruses can interact with a given Trim5α. While there are nearly no human polymorphisms in the recognition part of Trim5α, there is a very high frequency polymorphism in the human population that renders the effector part of the protein non-functional.

There is an ancient extinct retrovirus, called PtERV1, that is found in the genome of chimpanzees, gorillas, and many old world primates, but is completely missing from the genome of humans.  We would like to understand why humans did not get infected with this virus, and how the function of Trim5α has evolved such that it does not protect humans from HIV-1 infections.  

Other host defense genes--We are also identifying additional host defense genes and the evolutionary pressures that allow retroviruses to escape them.

Emerman, Michael (2006) Proc. Natl. Acad. Sci. USA 103, 5249-5250
Copyright ©2006 by the National Academy of Sciences